4 recherche sur le mot-clé 'Nerve Tissue Proteins/genetics/metabolism'

Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications / Jan Philipp DELLING in Journal of Neurodevelopmental Disorders, 13 (2021)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 13 (2021) Titre : Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications Type de document : texte imprimé Auteurs : Jan Philipp DELLING, Auteur ; Tobias M. BOECKERS, Auteur Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/genetics/therapy  Chromosome Deletion  Chromosome Disorders  Humans  Mice  Microfilament Proteins/genetics  Nerve Tissue Proteins/genetics/metabolism  Phenotype  Rats  asd  Autism spectrum disorder  pmds  Phelan-McDermid syndrome  shank3  Therapy Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. MAIN TEXT: This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. CONCLUSIONS: Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors. En ligne : https://dx.doi.org/10.1186/s11689-021-09397-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] Comparison of SHANK3 deficiency in animal models: phenotypes, treatment strategies, and translational implications [texte imprimé] / Jan Philipp DELLING, Auteur ; Tobias M. BOECKERS, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 13 (2021) Mots-clés : Animals  Autism Spectrum Disorder/genetics/therapy  Chromosome Deletion  Chromosome Disorders  Humans  Mice  Microfilament Proteins/genetics  Nerve Tissue Proteins/genetics/metabolism  Phenotype  Rats  asd  Autism spectrum disorder  pmds  Phelan-McDermid syndrome  shank3  Therapy Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition, which is characterized by clinical heterogeneity and high heritability. Core symptoms of ASD include deficits in social communication and interaction, as well as restricted, repetitive patterns of behavior, interests, or activities. Many genes have been identified that are associated with an increased risk for ASD. Proteins encoded by these ASD risk genes are often involved in processes related to fetal brain development, chromatin modification and regulation of gene expression in general, as well as the structural and functional integrity of synapses. Genes of the SH3 and multiple ankyrin repeat domains (SHANK) family encode crucial scaffolding proteins (SHANK1-3) of excitatory synapses and other macromolecular complexes. SHANK gene mutations are highly associated with ASD and more specifically the Phelan-McDermid syndrome (PMDS), which is caused by heterozygous 22q13.3-deletion resulting in SHANK3-haploinsufficiency, or by SHANK3 missense variants. SHANK3 deficiency and potential treatment options have been extensively studied in animal models, especially in mice, but also in rats and non-human primates. However, few of the proposed therapeutic strategies have translated into clinical practice yet. MAIN TEXT: This review summarizes the literature concerning SHANK3-deficient animal models. In particular, the structural, behavioral, and neurological abnormalities are described and compared, providing a broad and comprehensive overview. Additionally, the underlying pathophysiologies and possible treatments that have been investigated in these models are discussed and evaluated with respect to their effect on ASD- or PMDS-associated phenotypes. CONCLUSIONS: Animal models of SHANK3 deficiency generated by various genetic strategies, which determine the composition of the residual SHANK3-isoforms and affected cell types, show phenotypes resembling ASD and PMDS. The phenotypic heterogeneity across multiple models and studies resembles the variation of clinical severity in human ASD and PMDS patients. Multiple therapeutic strategies have been proposed and tested in animal models, which might lead to translational implications for human patients with ASD and/or PMDS. Future studies should explore the effects of new therapeutic approaches that target genetic haploinsufficiency, like CRISPR-mediated activation of promotors. En ligne : https://dx.doi.org/10.1186/s11689-021-09397-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs / Feipeng ZHU in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 9p. Titre : Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs Type de document : texte imprimé Auteurs : Feipeng ZHU, Auteur ; Qi SHI, Auteur ; Yong-hui JIANG, Auteur ; Yong Q. ZHANG, Auteur ; Hui ZHAO, Auteur Article en page(s) : 9p. Langues : Anglais (eng) Mots-clés : Humans  Dogs  Animals  Autistic Disorder/genetics  Autism Spectrum Disorder  Nerve Tissue Proteins/genetics/metabolism  Pyramidal Cells/metabolism  Synaptic Transmission/genetics  Prefrontal Cortex  Anxiety  Disease Models, Animal  Autism spectrum disorder  Dog  Excitability  Shank3  Synaptic transmission Index. décimale : PER Périodiques Résumé : BACKGROUND: SHANK3 gene is a highly replicated causative gene for autism spectrum disorder and has been well characterized in multiple Shank3 mutant rodent models. When compared to rodents, domestic dogs are excellent animal models in which to study social cognition as they closely interact with humans and exhibit similar social behaviors. Using CRISPR/Cas9 editing, we recently generated a dog model carrying Shank3 mutations, which displayed a spectrum of autism-like behaviors, such as social impairment and heightened anxiety. However, the neural mechanism underlying these abnormal behaviors remains to be identified. METHODS: We used Shank3 mutant dog models to examine possible relationships between Shank3 mutations and neuronal dysfunction. We studied electrophysiological properties and the synaptic transmission of pyramidal neurons from acute brain slices of the prefrontal cortex (PFC). We also examined dendrite elaboration and dendritic spine morphology in the PFC using biocytin staining and Golgi staining. We analyzed the postsynaptic density using electron microscopy. RESULTS: We established a protocol for the electrophysiological recording of canine brain slices and revealed that excitatory synaptic transmission onto PFC layer 2/3 pyramidal neurons in Shank3 heterozygote dogs was impaired, and this was accompanied by reduced dendrite complexity and spine density when compared to wild-type dogs. Postsynaptic density structures were also impaired in Shank3 mutants; however, pyramidal neurons exhibited hyperexcitability. LIMITATIONS: Causal links between impaired PFC pyramidal neuron function and behavioral alterations remain unclear. Further experiments such as manipulating PFC neuronal activity or restoring synaptic transmission in Shank3 mutant dogs are required to assess PFC roles in altered social behaviors. CONCLUSIONS: Our study demonstrated the feasibility of using canine brain slices as a model system to study neuronal circuitry and disease. Shank3 haploinsufficiency causes morphological and functional abnormalities in PFC pyramidal neurons, supporting the notion that Shank3 mutant dogs are new and valid animal models for autism research. En ligne : https://dx.doi.org/10.1186/s13229-024-00587-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538 [article] Impaired synaptic function and hyperexcitability of the pyramidal neurons in the prefrontal cortex of autism-associated Shank3 mutant dogs [texte imprimé] / Feipeng ZHU, Auteur ; Qi SHI, Auteur ; Yong-hui JIANG, Auteur ; Yong Q. ZHANG, Auteur ; Hui ZHAO, Auteur . - 9p. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 9p. Mots-clés : Humans  Dogs  Animals  Autistic Disorder/genetics  Autism Spectrum Disorder  Nerve Tissue Proteins/genetics/metabolism  Pyramidal Cells/metabolism  Synaptic Transmission/genetics  Prefrontal Cortex  Anxiety  Disease Models, Animal  Autism spectrum disorder  Dog  Excitability  Shank3  Synaptic transmission Index. décimale : PER Périodiques Résumé : BACKGROUND: SHANK3 gene is a highly replicated causative gene for autism spectrum disorder and has been well characterized in multiple Shank3 mutant rodent models. When compared to rodents, domestic dogs are excellent animal models in which to study social cognition as they closely interact with humans and exhibit similar social behaviors. Using CRISPR/Cas9 editing, we recently generated a dog model carrying Shank3 mutations, which displayed a spectrum of autism-like behaviors, such as social impairment and heightened anxiety. However, the neural mechanism underlying these abnormal behaviors remains to be identified. METHODS: We used Shank3 mutant dog models to examine possible relationships between Shank3 mutations and neuronal dysfunction. We studied electrophysiological properties and the synaptic transmission of pyramidal neurons from acute brain slices of the prefrontal cortex (PFC). We also examined dendrite elaboration and dendritic spine morphology in the PFC using biocytin staining and Golgi staining. We analyzed the postsynaptic density using electron microscopy. RESULTS: We established a protocol for the electrophysiological recording of canine brain slices and revealed that excitatory synaptic transmission onto PFC layer 2/3 pyramidal neurons in Shank3 heterozygote dogs was impaired, and this was accompanied by reduced dendrite complexity and spine density when compared to wild-type dogs. Postsynaptic density structures were also impaired in Shank3 mutants; however, pyramidal neurons exhibited hyperexcitability. LIMITATIONS: Causal links between impaired PFC pyramidal neuron function and behavioral alterations remain unclear. Further experiments such as manipulating PFC neuronal activity or restoring synaptic transmission in Shank3 mutant dogs are required to assess PFC roles in altered social behaviors. CONCLUSIONS: Our study demonstrated the feasibility of using canine brain slices as a model system to study neuronal circuitry and disease. Shank3 haploinsufficiency causes morphological and functional abnormalities in PFC pyramidal neurons, supporting the notion that Shank3 mutant dogs are new and valid animal models for autism research. En ligne : https://dx.doi.org/10.1186/s13229-024-00587-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538

Increased expression of the PI3K catalytic subunit p110delta underlies elevated S6 phosphorylation and protein synthesis in an individual with autism from a multiplex family / Ashwini C. POOPAL in Molecular Autism, 7 (2016)  

Public ISBD [article]  inMolecular Autism > 7 (2016) . - 3p. Titre : Increased expression of the PI3K catalytic subunit p110delta underlies elevated S6 phosphorylation and protein synthesis in an individual with autism from a multiplex family Type de document : texte imprimé Auteurs : Ashwini C. POOPAL, Auteur ; Lindsay M. SCHROEDER, Auteur ; Paul S. HORN, Auteur ; Gary J. BASSELL, Auteur ; Christina GROSS, Auteur Article en page(s) : 3p. Langues : Anglais (eng) Mots-clés : Adenine/analogs & derivatives/pharmacology  Autistic Disorder/enzymology/genetics/pathology  Biomarkers  Cell Line  Class I Phosphatidylinositol 3-Kinases/antagonists &  inhibitors/biosynthesis/genetics/physiology  Diseases in Twins  Enzyme-Linked Immunosorbent Assay  Family Health  Female  Humans  Lymphocytes/enzymology  Male  Molecular Targeted Therapy  Nerve Tissue Proteins/genetics/metabolism  Phosphorylation  Protein Processing, Post-Translational  Quinazolines/pharmacology  Ribosomal Protein S6 Kinases/metabolism  Signal Transduction/genetics  TOR Serine-Threonine Kinases/physiology  Autism  Biomarker  Ic87114  PI3K/mTOR signaling  S6 phosphorylation  p110delta Index. décimale : PER Périodiques Résumé : BACKGROUND: Dysfunctions in the PI3K/mTOR pathway have gained a lot of attention in autism research. This was initially based on the discovery of several monogenic autism spectrum disorders with mutations or defects in PI3K/mTOR signaling components. Recent genetic studies corroborate that defective PI3K/mTOR signaling might be a shared pathomechanism in autism disorders of so far unknown etiology, but functional molecular analyses in human cells are rare. The goals of this study were to perform a functional screen of cell lines from patients with idiopathic autism for defects in PI3K/mTOR signaling, to test if further functional analyses are suitable to detect underlying molecular mechanisms, and to evaluate this approach as a biomarker tool to identify therapeutic targets. METHODS: We performed phospho-S6- and S6-specific ELISA experiments on 21 lymphoblastoid cell lines from the AGRE collection and on 37 lymphoblastoid cell lines from the Simons Simplex Collection and their healthy siblings. Cell lines from one individual with increased S6 phosphorylation and his multiplex family were analyzed in further detail to identify upstream defects in PI3K signaling associated with autism diagnosis. RESULTS: We detected significantly increased S6 phosphorylation in 3 of the 21 lymphoblastoid cell lines from AGRE compared to a healthy control and in 1 of the 37 lymphoblastoid cell lines from the Simons Simplex Collection compared to the healthy sibling. Further analysis of cells from one individual with elevated S6 phosphorylation showed increased expression of the PI3K catalytic subunit p110delta, which was also observed in lymphoblastoid cells from other autistic siblings but not unaffected members in his multiplex family. The p110delta-selective inhibitor IC87114 reduced elevated S6 phosphorylation and protein synthesis in this cell line. CONCLUSIONS: Our results suggest that functional analysis of PI3K/mTOR signaling is a biomarker tool to identify disease-associated molecular defects that could serve as therapeutic targets in autism. Using this approach, we discovered impaired signaling and protein synthesis through the PI3K catalytic subunit p110delta as an underlying molecular defect and potential treatment target in select autism spectrum disorders. Increased p110delta activity was recently associated with schizophrenia, and our results suggest that p110delta may also be implicated in autism. En ligne : http://dx.doi.org/10.1186/s13229-015-0066-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] Increased expression of the PI3K catalytic subunit p110delta underlies elevated S6 phosphorylation and protein synthesis in an individual with autism from a multiplex family [texte imprimé] / Ashwini C. POOPAL, Auteur ; Lindsay M. SCHROEDER, Auteur ; Paul S. HORN, Auteur ; Gary J. BASSELL, Auteur ; Christina GROSS, Auteur . - 3p. Langues : Anglais (eng) in Molecular Autism > 7 (2016) . - 3p. Mots-clés : Adenine/analogs & derivatives/pharmacology  Autistic Disorder/enzymology/genetics/pathology  Biomarkers  Cell Line  Class I Phosphatidylinositol 3-Kinases/antagonists &  inhibitors/biosynthesis/genetics/physiology  Diseases in Twins  Enzyme-Linked Immunosorbent Assay  Family Health  Female  Humans  Lymphocytes/enzymology  Male  Molecular Targeted Therapy  Nerve Tissue Proteins/genetics/metabolism  Phosphorylation  Protein Processing, Post-Translational  Quinazolines/pharmacology  Ribosomal Protein S6 Kinases/metabolism  Signal Transduction/genetics  TOR Serine-Threonine Kinases/physiology  Autism  Biomarker  Ic87114  PI3K/mTOR signaling  S6 phosphorylation  p110delta Index. décimale : PER Périodiques Résumé : BACKGROUND: Dysfunctions in the PI3K/mTOR pathway have gained a lot of attention in autism research. This was initially based on the discovery of several monogenic autism spectrum disorders with mutations or defects in PI3K/mTOR signaling components. Recent genetic studies corroborate that defective PI3K/mTOR signaling might be a shared pathomechanism in autism disorders of so far unknown etiology, but functional molecular analyses in human cells are rare. The goals of this study were to perform a functional screen of cell lines from patients with idiopathic autism for defects in PI3K/mTOR signaling, to test if further functional analyses are suitable to detect underlying molecular mechanisms, and to evaluate this approach as a biomarker tool to identify therapeutic targets. METHODS: We performed phospho-S6- and S6-specific ELISA experiments on 21 lymphoblastoid cell lines from the AGRE collection and on 37 lymphoblastoid cell lines from the Simons Simplex Collection and their healthy siblings. Cell lines from one individual with increased S6 phosphorylation and his multiplex family were analyzed in further detail to identify upstream defects in PI3K signaling associated with autism diagnosis. RESULTS: We detected significantly increased S6 phosphorylation in 3 of the 21 lymphoblastoid cell lines from AGRE compared to a healthy control and in 1 of the 37 lymphoblastoid cell lines from the Simons Simplex Collection compared to the healthy sibling. Further analysis of cells from one individual with elevated S6 phosphorylation showed increased expression of the PI3K catalytic subunit p110delta, which was also observed in lymphoblastoid cells from other autistic siblings but not unaffected members in his multiplex family. The p110delta-selective inhibitor IC87114 reduced elevated S6 phosphorylation and protein synthesis in this cell line. CONCLUSIONS: Our results suggest that functional analysis of PI3K/mTOR signaling is a biomarker tool to identify disease-associated molecular defects that could serve as therapeutic targets in autism. Using this approach, we discovered impaired signaling and protein synthesis through the PI3K catalytic subunit p110delta as an underlying molecular defect and potential treatment target in select autism spectrum disorders. Increased p110delta activity was recently associated with schizophrenia, and our results suggest that p110delta may also be implicated in autism. En ligne : http://dx.doi.org/10.1186/s13229-015-0066-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

Shank3 deficiency elicits autistic-like behaviors by activating p38? in hypothalamic AgRP neurons / Shanshan WU in Molecular Autism, 15 (2024)  

Public ISBD [article]  inMolecular Autism > 15 (2024) . - 14p. Titre : Shank3 deficiency elicits autistic-like behaviors by activating p38? in hypothalamic AgRP neurons Type de document : texte imprimé Auteurs : Shanshan WU, Auteur ; Jing WANG, Auteur ; Zicheng ZHANG, Auteur ; Xinchen JIN, Auteur ; Yang XU, Auteur ; Youwen SI, Auteur ; Yixiao LIANG, Auteur ; Yueping GE, Auteur ; Huidong ZHAN, Auteur ; Li PENG, Auteur ; Wenkai BI, Auteur ; Dandan LUO, Auteur ; Mengzhu LI, Auteur ; Bo MENG, Auteur ; Qingbo GUAN, Auteur ; Jiajun ZHAO, Auteur ; Ling GAO, Auteur ; Zhao HE, Auteur Article en page(s) : 14p. Langues : Anglais (eng) Mots-clés : Animals  Mice  Agouti-Related Protein/genetics/metabolism  Arcuate Nucleus of Hypothalamus/metabolism  Autistic Disorder/genetics/metabolism  Hypothalamus/metabolism  Microfilament Proteins/metabolism  Nerve Tissue Proteins/genetics/metabolism  Neurons/metabolism  Mitogen-Activated Protein Kinase 14/metabolism  AgRP  Autism  Shank3  Sociability  Stereotypic behavior  p38? Index. décimale : PER Périodiques Résumé : BACKGROUND: SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) monogenic mutations or deficiency leads to excessive stereotypic behavior and impaired sociability, which frequently occur in autism cases. To date, the underlying mechanisms by which Shank3 mutation or deletion causes autism and the part of the brain in which Shank3 mutation leads to the autistic phenotypes are understudied. The hypothalamus is associated with stereotypic behavior and sociability. p38 , a mediator of inflammatory responses in the brain, has been postulated as a potential gene for certain cases of autism occurrence. However, it is unclear whether hypothalamus and p38 are involved in the development of autism caused by Shank3 mutations or deficiency. METHODS: Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and immunoblotting were used to assess alternated signaling pathways in the hypothalamus of Shank3 knockout (Shank3(-/-)) mice. Home-Cage real-time monitoring test was performed to record stereotypic behavior and three-chamber test was used to monitor the sociability of mice. Adeno-associated viruses 9 (AAV9) were used to express p38 in the arcuate nucleus (ARC) or agouti-related peptide (AgRP) neurons. D176A and F327S mutations expressed constitutively active p38 . T180A and Y182F mutations expressed inactive p38 . RESULTS: We found that Shank3 controls stereotypic behavior and sociability by regulating p38 activity in AgRP neurons. Phosphorylated p38 level in hypothalamus is significantly enhanced in Shank3(-/-) mice. Consistently, overexpression of p38 in ARC or AgRP neurons elicits excessive stereotypic behavior and impairs sociability in wild-type (WT) mice. Notably, activated p38 in AgRP neurons increases stereotypic behavior and impairs sociability. Conversely, inactivated p38 in AgRP neurons significantly ameliorates autistic behaviors of Shank3(-/-) mice. In contrast, activated p38 in pro-opiomelanocortin (POMC) neurons does not affect stereotypic behavior and sociability in mice. LIMITATIONS: We demonstrated that SHANK3 regulates the phosphorylated p38 level in the hypothalamus and inactivated p38 in AgRP neurons significantly ameliorates autistic behaviors of Shank3(-/-) mice. However, we did not clarify the biochemical mechanism of SHANK3 inhibiting p38 in AgRP neurons. CONCLUSIONS: These results demonstrate that the Shank3 deficiency caused autistic-like behaviors by activating p38 signaling in AgRP neurons, suggesting that p38 signaling in AgRP neurons is a potential therapeutic target for Shank3 mutant-related autism. En ligne : https://dx.doi.org/10.1186/s13229-024-00595-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538 [article] Shank3 deficiency elicits autistic-like behaviors by activating p38? in hypothalamic AgRP neurons [texte imprimé] / Shanshan WU, Auteur ; Jing WANG, Auteur ; Zicheng ZHANG, Auteur ; Xinchen JIN, Auteur ; Yang XU, Auteur ; Youwen SI, Auteur ; Yixiao LIANG, Auteur ; Yueping GE, Auteur ; Huidong ZHAN, Auteur ; Li PENG, Auteur ; Wenkai BI, Auteur ; Dandan LUO, Auteur ; Mengzhu LI, Auteur ; Bo MENG, Auteur ; Qingbo GUAN, Auteur ; Jiajun ZHAO, Auteur ; Ling GAO, Auteur ; Zhao HE, Auteur . - 14p. Langues : Anglais (eng) in Molecular Autism > 15 (2024) . - 14p. Mots-clés : Animals  Mice  Agouti-Related Protein/genetics/metabolism  Arcuate Nucleus of Hypothalamus/metabolism  Autistic Disorder/genetics/metabolism  Hypothalamus/metabolism  Microfilament Proteins/metabolism  Nerve Tissue Proteins/genetics/metabolism  Neurons/metabolism  Mitogen-Activated Protein Kinase 14/metabolism  AgRP  Autism  Shank3  Sociability  Stereotypic behavior  p38? Index. décimale : PER Périodiques Résumé : BACKGROUND: SH3 and multiple ankyrin repeat domains protein 3 (SHANK3) monogenic mutations or deficiency leads to excessive stereotypic behavior and impaired sociability, which frequently occur in autism cases. To date, the underlying mechanisms by which Shank3 mutation or deletion causes autism and the part of the brain in which Shank3 mutation leads to the autistic phenotypes are understudied. The hypothalamus is associated with stereotypic behavior and sociability. p38 , a mediator of inflammatory responses in the brain, has been postulated as a potential gene for certain cases of autism occurrence. However, it is unclear whether hypothalamus and p38 are involved in the development of autism caused by Shank3 mutations or deficiency. METHODS: Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and immunoblotting were used to assess alternated signaling pathways in the hypothalamus of Shank3 knockout (Shank3(-/-)) mice. Home-Cage real-time monitoring test was performed to record stereotypic behavior and three-chamber test was used to monitor the sociability of mice. Adeno-associated viruses 9 (AAV9) were used to express p38 in the arcuate nucleus (ARC) or agouti-related peptide (AgRP) neurons. D176A and F327S mutations expressed constitutively active p38 . T180A and Y182F mutations expressed inactive p38 . RESULTS: We found that Shank3 controls stereotypic behavior and sociability by regulating p38 activity in AgRP neurons. Phosphorylated p38 level in hypothalamus is significantly enhanced in Shank3(-/-) mice. Consistently, overexpression of p38 in ARC or AgRP neurons elicits excessive stereotypic behavior and impairs sociability in wild-type (WT) mice. Notably, activated p38 in AgRP neurons increases stereotypic behavior and impairs sociability. Conversely, inactivated p38 in AgRP neurons significantly ameliorates autistic behaviors of Shank3(-/-) mice. In contrast, activated p38 in pro-opiomelanocortin (POMC) neurons does not affect stereotypic behavior and sociability in mice. LIMITATIONS: We demonstrated that SHANK3 regulates the phosphorylated p38 level in the hypothalamus and inactivated p38 in AgRP neurons significantly ameliorates autistic behaviors of Shank3(-/-) mice. However, we did not clarify the biochemical mechanism of SHANK3 inhibiting p38 in AgRP neurons. CONCLUSIONS: These results demonstrate that the Shank3 deficiency caused autistic-like behaviors by activating p38 signaling in AgRP neurons, suggesting that p38 signaling in AgRP neurons is a potential therapeutic target for Shank3 mutant-related autism. En ligne : https://dx.doi.org/10.1186/s13229-024-00595-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=538